Optimizing the Perioperative Management of Breast Cancer

Denise A. Yardley, MD:The role of radiation therapy in adjuvant and neoadjuvant settings has been on the increase. I think we’ve really seen the value of radiation therapy in cases for which we previously did not even offer radiation therapy. This particular patient had no lymph node involvement. I think a patient with high-risk disease, in terms of having a HER2-positive biology, is definitely a patient who I would offer adjuvant radiation therapy to. I think when we look at the role of radiation in these patients, it clearly would decrease the risk of local regional recurrence. There’s a suggestion that it may help improve disease-free survival, but it’s really done with the goal of minimizing the local regional recurrence.

In this particular patient scenario, if we change her hormone receptor status and make her a hormone receptor-positive, HER2-positive patient—now known as a triple-positive breast cancer—there would be some different considerations. I would have expected a higher risk or amount of disease burden at the time of surgery. We know there are less pathologic complete responses in the HER2-positive, hormone receptor-positive patients. We also know that their risk of recurrence is a little bit higher.

I think the role for this patient would then be in the adjuvant setting, and I would definitely have added an anti-estrogen therapy for this patient. I think there was a trial that looked at adding it up front because we know that this disease has a signaling pathway that may bypass the benefits of some of the HER2-targeted therapies. They actually looked at adding adjuvant endocrine therapy up front in the neoadjuvant setting to see if blocking 2 different signaling pathways in these triple-positive tumors would result in better outcomes, and it did not.

An aromatase inhibitor is what I typically use in my HER2-positive patients in the adjuvant setting, and I would start that after surgery in combination with her dual HER2-targeted therapy. In the hormone receptor-positive, HER2-positive patients, I think there are some new data for extended HER2-targeted therapy with neratinib. I think the data clearly don’t fit this particular patient because the neratinib study was not done in patients who had received prior pertuzumab. I always talk to my patients about how there is another therapy that has been approved. When we look at the subset analysis of that particular trial that tested neratinib, an oral HER2-targeted agent, following a year of the HER2-targeted therapy, at that time the trials were all Herceptin [trastuzumab]-based, so the standard wasn’t dual HER2-targeted therapy. The patients did not get Herceptin and Perjeta [pertuzumab], so it’s difficult to extrapolate.

The benefit was quite small, on the magnitude of 1% to 2%. The hormone receptor-positive subgroup suggested that they benefited from the extended HER2-targeted therapy following their year of Herceptin. I’ve mentioned it to patients. I have not prescribed it to patients. I talk about the caveats. We don’t know if there is benefit in a patient who has already received pertuzumab. And then, we do talk about the adverse effects of neratinib, which include a fairly substantial risk of diarrhea. When these patients are now a year from completing their therapy and are looking at another year of potential quality of life issues from toxicity with an unknown benefit, most aren’t excited about going on to neratinib either.

This patient was a HER2-positive, hormone receptor-negative patient who was appropriate for neoadjuvant therapy and continued to receive and complete a year of adjuvant HER2-targeted therapy. Looking at what the future may hold for this patient population is challenging because the outcomes are so great now with the addition of HER2-targeted therapy. Even if we look at the APHINITY trial, where pertuzumab was given in the adjuvant setting completely, we’re looking at survival and disease-free survival of 90% or more. It’s hard to see how we’re going to further affect that or increase that.

We do have some novel HER2-targeted agents and novel drug antibody conjugates that have made it into the adjuvant setting, and we’re trying to stratify now which HER2-positive patient requires which chemotherapy and dual HER2-targeted therapy. There have been some trials in node-negative small tumors, whether we could just use a taxane and Herceptin-based regimen. They’ve explored the role of potentially using T-DM1 or calcyon-targeted therapy in that population, which has less overall systemic toxicity for the patient. Trials are looking at elderly HER2-positive patients, and can we approach them differently depending on low-risk disease versus high-risk, HER2-positive disease.

I think we’re now able to really focus on the subgroups of the HER2-positive patients. I think the biggest take-away is now trying to deescalate therapy. Does everybody need the one-size-fits all chemotherapy regimen, or can we start paring it down to be a single chemotherapy agent with dual HER2-targeted therapy or just monotherapy? Future strategies are looking at trying to strip some therapy recommendations away and tailor it to a node-negative, elderly patient with hormone receptor-positive disease.

Transcript edited for clarity.

A 56-Year-Old Woman Receiving Adjuvant Therapy forHER2+ Breast Cancer

• A 56-year-old postmenopausal woman was referred for evaluation of a left-sided spiculated mass (2.4-cm) with scattered microcalcifications, found incidentally on screening mammography. Mammogram 12 months earlier was normal.
• Ultrasound confirmed a hypoechoic mass of approximately 2.4 cm X 2,3 cm by 1.8 cm at the 2 o’clock position in the left breast, 4 cm from the nipple. Axillary ultrasound demonstrated 3 enlarged lymph nodes with cortex thickening.
• Core biopsy of the breast mass revealed poorly differentiated invasive ductal carcinoma, ER/PR-negative, HER2 IHC 3+; lymph node sampling revealed the presence of breast cancer.
• Staging: T2N1M0
• She received neoadjuvant docetaxel and carboplatin with concurrent trastuzumab and pertuzumab.
• Surgical resection scattered microscopic foci of residual disease spanning 4 mm; no involved lymph nodes
  • Re-staging, ypT1aypN0M0